Animal feed and process

ABSTRACT

AN ANIMAL FEED COMPRISING A COMPOUND OF THE GROUP CONSISTING OF A 3H-1,4-BENZODIAZEPINE OF THE FORMULA:   2-(R-O-NH-),5-(R3,R4-PHENYL),R1,R2-3H-1,4-BENZODIAZEPINE   WHEREIN R IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, LOWER-ALKYL OF 1 TO 4 CARBON ATOMS, INCLUSIVE, LOWERALKENYL OF 3 OR 4 CARBOM ATOMS, BENZYL, -H2CCOOH AND -(CH2)2COOH AND THE ESTERS THEREOF DERIVED FROM AN ALKANOL OF 1 TO 3 CARBON ATOMS, INCLUSIVE; AND   -(CH2)N-N(-R5)-R6   IN WHICH N IS 3 OR 4 AND R5 AND R6 ARE LOWER-ALKYL OF 1 TO 4 CARBON ATOMS, INCLUSIVE, OR R5 AND R6 TOGETHER ARE ALYLENE OF 4 OR 5 CARBON ATOMS, AND WHEREIN R1, R2, R3, AND R4 ARE SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, LOWER ALKOXY OF 1 TO 3 CARBON ATOMS, INCLUSIVE, ALKYL DEFINED AS ABOVE, ALKYTHIO IN WHICH THE ALKYL GROUP IS DEFINED AS ABOVE, HALOGEN, NITRO, CYANO AND -CF3; AND PHARMACOLOGICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF IN COMBINATION WITH THE NUTRIENT FEED.

3,755,577 ANIMAL FEED AND PROCESS Robert J. Collins, Portage, Mich., assignor to The Upjohn Company, Kalamazoo, Mich. No Drawing. Filed Aug. 9, 1971, Ser. No. 170,324 Int. Cl. A61k 27/00 U.S. Cl. 424-244 12 Claims ABSTRACT OF THE DISCLOSURE An animal feed comprising a compound of the group consisting of a 3H-l,4-benzodiazepine of the formula:

Formula 1 wherein R is selected from the group consisting of hydrogen, lower-alkyl of 1 to 4 carbon atoms, inclusive, loweralkenyl of 3 or 4 carbon atoms, benzyl, -H CCOOH and (CH COOH and the esters thereof derived from an alkanol of 1 to 3 carbon atoms, inclusive, and

u in which n is 3 or 4 and R and R are lower-alkyl of 1 to 4 carbon atoms, inclusive, or R and R together are alkylene of 4 or 5 carbon atoms, and wherein R R R and R are selected from the group consisting of hydro gen, lower alkoxy of 1 to 3 carbon atoms, inclusive, alkyl defined as above, alkylthio in which the alkyl group is defined as above, halogen, nitro, cyano and --CF;,; and pharmacologically acceptable acid addition salts thereof in combination with the nutrient feed.

CROSS REFERENCE TO RELATED APPLICATIONS This application is related to copending U.S. application Ser. No. 56,750, filed July 20, 1970, now Patent No. 3,649,617, which discloses compounds of the Formula 1 and methods fortheir preparation.

BRIEF SUMMARY OF THE INVENTION Broadly the present invention encompasses a nutrition-' ally adeqaute animal feed having dispersed therein a compound of the Formula 1 in suflicient concentration to provide increasing productivity and feed efiiciencies in healthy meat-producing, milk-producing or egg-laying animals. The invention also includes the process of feeding the composition to meat-producing, milk-producing or egg-laying animals.

DETAILED DESCRIPTION It has been found in recent years that meat-producing animals will gain more weight and gain it faster when various classes of compounds such as vitamins, minerals, estrogens, antibiotics, and tranquilizers are added to the diet. Although the presently avaiable compounds are useful, new materials are still being sought that would produce weight gains more rapidly, to a greater extent, more efficiently with respect to feed intake at a lower cost and without undesirable side effects.

It is now possible by use of the present invention to obtain unexpected results in the feeding of meat-produc- United States Patent 0 ing, milk-producing, or egg-laying animals; that is to say, an increased rate of weight gain, an increased amount of weight gain, an increase in milk production, or increased rate of egg laying, as well as increased feed efficiency, can be obtained by the addition of minute quantities of a compound of the Formula 1 to the animals usual nutrient feed.

Compounds of the Formula 1 can be prepared by methods disclosed in U.S. application Ser. No. 56,750, now Patent No. 3,649,617, filed July 20, 1970.

Unless otherwise specified, all percentages are given on a weight-to-weight basis. The pound (1b.) weights given are avoirdupois units.

Feeding of the compositions of the present invention can commence for birds shortly after hatching and in the case of mammals, during the creep-feeding period of suckling animals when they are starting on solid food and, of course, after weaning. Feeding of the compositions is continued throughout the growing period, lactation period, or egg-laying period.

The total concentration of the compound of the Formula 1 in the feed composition is determined with regard to the species of animal, age, weight, and average amount of feed consumed daily. Preferably the compound of the Formula 1 is employed in the finished feed that will supply the animal with a daily intake of from about 0.015 mg. to about 250 mg. per head per day.

The following table illustrates the range of compound of Formula 1 in milligrams daily dose per head per day for representative animals.

Range daily Preferred dose/head, daily Animal mg. dose, mg.

Swine (birth to 8 weeks) 0 125-12. 5 0. 7 swine (40 to 200 lbs.) 0 725-72. 5 4. 0 Chickens (growing 0-8 weeks 0 015-1. 6 0. 1 Hens (laying) 0. 03-3. 0 0. 16 Turkeys (growing ()24 Weeks) 0. 1-6. 0 0. 25 Beef cattle (fattening) 2. 5-250 14. 0 Calves (0-12 weeks) 0. 3-30 1. 5 Dairy cattle (lactatio 2. 6-250 14. 0 Lambs (fattening) 0. 19-19 1. 0

The foregoing dosage can generally be accomplished by providing from about mg. to about 12,500 mg. of a compound of the Formula 1 per ton of finished feed.

Advantageously a compound of the Formula 1 is supplied in the form of a liquid or solid premix wherein the concentration is -2000 times greater than the desired final concentration of the feed. For example, the compound of Formula 1 can be dissolved or suspended in a fluid vehicle such as corn oil, cottonseed oil, molasses, distillers solubles and the like to prepare a fluid premix. Alternatively, a solid premix can be prepared by mixing a compound of the Formula 1 with an edible solid diluent such as sucrose, lactose, starch, corn meal, flour, calcium carbonate, soybean meal and the like.

Example 1 A diet for fattening lambs is prepared from the following types and amounts of ingredients:

Contains the following percent of minerals: Mn, 12; Co, 0.08; Fe, 5.0; Cu, 0.4; I, 0.24 Zn, 0 7

The above feed to be mixed, pelleted and offered to fattening lambs free-choice in conjunction with hay.

A chicken feed for broilers is prepared from the following types and amounts of ingredients:

Percent Yellow corn meal 67.35 Soybean oil meal 24.00 Menhaden fish meal 6.00 Steamed bone meal 1.00 Ground limestone 1.00 Iodized salt .34 25% Choline chloride .13 Vitamin B supplement (6 mg./lb.) .10 Manganese sulfate .02 Supplemental vitamin mix 1 .06

Consisting of 16.0 gm. Vitamin A supplement (10 units/ mg.); 3.6 gm. Vitamin D3 supplement (15,000 units/gm.); 7.1 gm. riboflavin supplement (1 gm. riboflavin per ounce); 500 mg. niacin.

To 999 parts of the preceding feed is added 1 part of a premix composition prepared by mixing 1.0 gm. 2- [(allyloxy)amino1-7-chloro (o-chlorophenyl)-3H- l,4-benzodiazepine with suflicient soybean mill feed to make 1 pound.

The feeding composition so prepared supplies 1.0 mg. of 2-[(allyloxy)amino]-7-chloro 5 (o-chlorophenyl)- 3H-l,4-benzodiazepine per pound, or about 2.2 parts per million.

The foregoing composition is usefully fed to chickens for increased rate of weight gain and improved utilization of feed. Similarly the composition can be fed to turkeys, ducks and geese.

Example 3 A fattening feed for 800 pound yearling cattle is prepared from the following types and amounts of ingredients:

Contains the following percent of minerals: Mn, 12; Co, 0.08; Fe, 5.0; Cu, 0.4; I, 0.24; Zn, 0.7.

To 999 parts of the preceding feed is added 1 part of a premix composition prepared by mixing 1.5 gm. of 2- [(allyloxy) amino1-7-chloro 5 (o-chlorophenyl) 3H- ],4 benzodiazepine with sufficient wheat flour to make 1 pound.

The feeding composition so prepared supplies 1.5 mg. of 2-[(allyloxy)amino]-7-chloro 5 (o-chlorophenyD- 3H-l,4-benzodiazepine per pound, or about 3.3 parts per million.

Cattle are to receive the foregoing feed ad libitum together with 5 lb. of hay per head per day and when so fed have an increased rate of weight gain and improved utilization of feed.

Example 4 A swine diet for growing hogs of 40 to 100 pounds body weight is prepared from the following types and am u ts of ing d eets;

Percent Corn, ground 78.15 Soybean oil meal, 44% 17.0 Meat and bone scraps, 50% 3.0 Oyster shell flour 0.4 Bone meal 0.5 Salt 0.5 Trace mineral mixture 1 0.05 Zinx oxide 0.01 Vitamin A and D supplement 2 0.25 B Vitamin supplement 3 0.05 Vitamin B supplement 4 0.09

Contains the following percent of minerals: Mn, 12; Co, 0.08; Fe, 5.0; Cu, 0. 1; I, 0.24. Zn, 0.7.

-' Contains 300 USP units Da/gm. and 1500 I.U.A./gm.

(Iontains per 1b.: riboflavin, 2000 mg; calcium pantothenate, 4000 mg.; niacin, 9000 mg; and choline chloride 10,000 mg.

4 Contains 6 mg. Vitamin B12 per lb.

To 999 parts of the preceding feed is added 1 part of a premix composition prepared by mixing 0.75 gm. of 2-[(allyloxy)amino] 7 chloro-S-(o-chlorophenyD- 3H-l,4-benzodiazepine with sufiicient ground limestone to make one pound.

The feeding composition so prepared supplies 0.75 mg. of 2-[(allyloxy)amino] 7 chloro-S-(o-chlorophenyl) 3Hl,4-benzodiazepine per pound, or about 1.65 parts per million.

The foregoing composition is usefully fed to hogs for increased rate of weight gain and improved utilization of feed.

Example 5 Following the procedure of the preceding Examples 1 to 4, inclusive, animal feeds are similarly prepared substituting equimolar amounts of:

2- methoxyamino) -7-chloro-5-phenyl-3H-1,4-benzodiazepine;

2-(benzyloxyamino)-7-chloro-5-phenyl-3H-1,4-benzodiazepine; I

2- [2-( l-pyrrolidinyl) ethoxyam ino -7- chloro-S-phenyl- 3 H- 1 ,4-benzodi aze pine and hydrate thereof;

2-(t-butoxyamino)-7-chloro-5-phenyl-3H-1,4-benzodiazepine;

2- a1 lyloxyamino -7-chloro-5-phenyl-3 H- 1,4-benzodiazepine;

2- [2-( diethylamino) ethoxyamino] -7-chloro-5-phenyl-3H- 1,4-benzodiazepine and hernihydrate thereof;

ethyl (7-chloro-5-phenyl-3H- 1,4-benzodi azepin-Z-yl aminooxy] acetate;

Z-(hydroxyarniuo)-7-chloro-5-phenyl-3H1,4-benzodiazepine;

2- (methoxyamino -7-chloro-5- (o-chlorophenyl) -3H-l,4-

benzodiazepine;

[ (7 -chloro-5 -phenyl-3 H- 1,4 -benzodiazepine-2-yl) -aminooxy] acetic acid;

2-(ethoxyamino)-7-bromo-5-phenyl-3H-1,4-benzodiazepine;

2- butoxyamino) -7-trifluoromethyl-5- (o-chlorophenyl 3H- 1,4-benzodiazepine;

2- [3-( l-pyrrolidinyl) propoxyamino] -7-cyano-5- (o-fiuorophenyl -3 H- 1,4-benzodiazepine;

2 [2- l-piperidinyl) ethoxyamino1-7-nitro-5- (o-bromophenyl -3 H-l ,4-benzodiazepine;

Z-(hydroxyamino) -7-fiuoro-5-phenyl-3H-1,4-benzodiazepine; 1..

2- crotyloxyamino) -5-phenyl-3H l ,4-benzodiazepine 2- (propoxyamino -7-methyl-5 (o-fluorophenyl) 3H- 1,4-

benzodiazepine;

2- [3- dimethylamino propoxyamino]-7-trifiuoromethyl- 5-(o-chlorophenyl) -3H-1 ,4-benzodiazepine;

3-[ 7 -fiuoro-5-phenyl-3 H-l ,4-benzodiazepine-2-yl amino oxy propionic acid;

methyl [7-bromo-5-phenyl-3H- l ,4-benzodiazepin-2-yl aminooxy] acetate;

2- (isobutoxy amino) -7-cyano-5-pheny1-3H- 1 ,4-benzodiazepine;

2-[ (allyloxy) amino] -7-nitro-5- (o-chlorophenyl) -3H- 1 ,4-

benzodiazepine;

2- (allyloxy) amino] -5-(o-chlorophenyl -3H-1 ,4-benzodiazepine;

2-[ (allyloxy) amino] -5-(2,6-dichlorophenyl) -3H-1 ,4-

benzodiazepine;

2- (allyloxy) amino] -5- 2,6-difluorophenyl -3H- 1 ,4-

benzodiazepine;

2- (allyloxy) amino] -5-(o-fluorophenyl) -3H-1,4-benzodiazepine;

7,9-dichloro-2- (methoxyamino) -5- (2,6-dichlrophenyl) 3H-1,4-benzodiazepine;

6,7-dicyano-2- (ethoxyarnino (m-nitrophenyl -3 H- l ,4-

benzodiazepine;

2- (t-butoxyamino -7,9-dichloro-5- (2,6-dichlorophenyl) 3H-1,4-benzodiazepine;

2- (propoxyamino) -6-methyl-7-bromo-5- (p-methylphenyl) -3H-1,4-benzodiazepine;

2- (allyloxy amino] -7-trifiuoromethyl-8-cyano-5- (2- chloro-S-methylphenyl) -3H-1,4-benzodiazepine;

2- [3- (diethylamino propoxyamino] -7,9-dicyano-5- 2,4-

dibromophenyl)-3H-1,4-benzodiazepine;

2-[ (allyloxy) amino] -8-nitro-5- (o-chlorophenyl -3H- 1,4-benzodiazepine;

2- (isopropoxyamino -7-chloro-5- (2-chloro-4-methylphenyl) -3H-1,4-benzodiazepine;

2-[ (benzyloxy) amino] -6,8-dimethyl-5 3,5 -diethoxyphenyl) -3H-1,4-benzodiazepine;

2-[ (allyloxy) amino] -7-ethyl-5- (o-butylphenyl) -2H-1 ,4-

benzodiazepine;

2- (allyloxy) amino] -7,8-dipropyl-5- (o-methylthiophenyl) -2H-1 ,4-benzodiazepine;

6-butylthio-2- (ethoxyamino -5- (p-propoxyphenyl -2H- 1,4-benzodiazepine;

2- (allyloxy) amino] -9-methylthio-7-bromo-5- 3 ,5 -difluorophenyl) -2H-1,4-benzodiazepine;

9-isopropyl-7-nitro-2-[ (allyloxy) amino] -5- 2,6-bis- (ethylthio)phenyl]-2H-1,4-benzodiazepine;

2- (allyloxyamino) -7-bromo-5-phenyl-3H-1,4-benzodiazepine;

2- (3-butenyloxy) amino] -7-trifluoromethyl-5- (o-chlorophenyl) -3H-1,4-benzodiazepine;

2- (isopropoxyamino -7-butyl-5-phenyl-3 H-1,4-benzodiazepine;

2- (benzyloxyamino) -7-fiuoro5- (o-bromophenyl) -3H- 1,4-benzodiazepine 2-(ethoxyamino) -7-chloro-5-(oafluorophenyl) -3H-1,4-

benzodiazepine;

2-(propoxyamino)-7-cyano-5-phenyl-3H-1,4-benzodiazepine;

2-(butoxyamino)-7-nitro-5-pheny1-3H-1,4-benzodiazepine;

2-(isopropoxyamino)-5-(o-bromophenyl)-3H-1,4-benzodiazepine;

2- [3-( l-piperidinyl)propoxyamino]-5-phenyl-3H-1,4-

benzodiazepine;

2- [2- (dirnethylamino) ethoxyamino] -5- (o-fiuorophenyl 3H-1,4-benzodiazepine;

2-(allyloxyamino) -7-nitro-5-phenyl-3H-1,4-benzodiaze- Z-lfydroxyamino-7-cyano-5-(o-bromophenyl)-3H-1,4-

benzodiazepine;

2-hydroxyamino-6,7-difiuoro-5- 3 ,5 (trifiuoromethyl phenyl] -3H-1,4-benzodiazepine;

2-benzyloxyamino-7,9-dicyano-5- (2,4-dibromophenyl) 3H-1,4-benzodiazepine;

2-butoxyamino-6,7-dicyano-5-(m-nitrophenyl)-3H-1,4-

benzo diazepine;

2- (allyloxy) amino] -7,9-dichloro-5- (2,6-dichlorophenyl)-3H-1,4-benzodiazepine;

2- (crotyloxy) amino] -7,9-d.ichloro-5-2,6-dichlorophenyl) -3H-1,4-benzodiazepine; for the 2- (allyloxy) amino] -7-chloro-5- (o-chlorophenyl -3H- 1 ,4-benzodiazepine of the examples.

I claim:

1. An animal feed for increasing productivity and feed efiiciencies in healthy meat-producing, milk-producing or egg-laying animals comprising a member selected from the group consisting of a 3H-1,4-benzodiazepine of the formula:

wherein R is selected from the group consisting of hydrogen, lower-alkyl of 1 to 4 carbon atoms, inclusive, loweralkenyl of 3 or 4 carbon atoms, benzyl, --H CCOOH and --(CH COOH and the esters thereof derived from an alkanol of 1 to 3 carbon atoms, inclusive, and

Ra in which n is 2 or 3 and R and R are lower-alkyl of 1 to 4 carbon atoms, inclusive, or R and R together signify the pyrrolidino or piperidino radical, and wherein R R R and R are selected from the group consisting of hydrogen, lower alkoxy of 1 to 3 carbon atoms, inclusive, alkyl defined as above, alkylthio in which the alkyl group is defined as above, halogen, nitro, cyano and --CF and the pharmacologically acceptable acid addition salts thereof in combination with the nutrient feed in an amount of from about 75 mg. to about 12,500 mg. of the said member per ton of feed.

2. A composition of claim 1 wherein the member selected is in a concentration of from mg. to 12,500 mg. per pound of nutrient carried in the form of a premix.

3. A composition of claim 1 when the member selected is in the concentration from 250 mg. to 25,000 mg. per ton of feed.

4. A composition of claim 1 wherein the compound is 2-[(allyloxy)amino]-7-ch1oro 5 (o-chlorophenyl)-3H- 1,4-benzodiazepine.

5. A composition of claim 2 wherein the compound is 2-[(allyloxy)amino] 7 chloro-S-(o-chlorophenyl)-3H- 1,4-benzodiazepine.

6. A composition of claim 3 wherein the compound is 2-[(allyloxy)amino] 7 chloro-S-(o-chlorophenyl)-3H- 1,4-benzodiazepine.

7. A process for increasing productivity and feed efficiencies in healthy, meat-producing, milk-producing or egg-laying animals comprising the feeding of from about 0.015 to about 250 mg./ day of a compound selected from the group consisting of a 3H-1,4-benzodiazepine of the formula:

NH-OR wherein R is selected from the group consisting of hydrogen, lower-alkyl of 1 to 4 carbon atoms, inclusive, loweralkenyl of 3 or 4 carbon atoms, benzyl, H CCOOH and -(CH COOH and the esters thereof derived from an alkanol of 1 to 3 carbon atoms, inclusive, and

in which n is 2 or 3 and R and R are lower-alkyl of 1 to 4 carbon atoms, inclusive, or R and R together signify the pyrrolidino or piperidino radical, and wherein R R R and R are selected from the group consisting of hydrogen, lower alkoxy of 1 to 3 carbon atoms, inclusive, alkyl defined as above, alkylthio in which the alkyl group is defined as above, halogen, nitro, cyauo and -CF and the pharmacologically acceptable acid addition salts thereof in combination with the nutrient feed to a healthy meat-producing, milk-producing or egg-laying animal.

8. A process of claim 7 wherein the member selected is in a concentration of from 125 mg. to 12,500 mg. per pound of nutrient carrier in the form of a premix.

9. A process of claim 7 when the member selected is in 8 the concentration from 250 mg. to 25,000 mg. per ton of feed.

10. A process of claim 7 wherein the compound is 2-[allyloxy)arnino] 7 chloro-S-(o-ch1orophenyl)3H- 1,4-benzodiazepine.

11. A process of claim 8 wherein the compound is 2-[(a1lyloxy)amino] 7 chloro-S-(o-chlorophenyl)-3H- 1,4-benzodiazepine.

12. A process of claim 9 wherein the compound is 2-[(a*llyloXy)amino] 7 chloro-5-(0-chlorophenyD-3H- 1,4-benzodiazepine.

References Cited UNITED STATES PATENTS 3,573,282 3/1971 Szmuszkovicz 424248 ALBERT T. MEYERS, Primary Examiner F. E. WADDELL, Assistant Examiner US. Cl. X.R. 424-267, 274

, UNITED STATES. PATENT OFFICE CERTIFICATE OF COREQTWN Patent 3,755 ,577 Dated Auqust 28. 1973 '6 Inventofls) Robert J an] 1 ins It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column l line 33, "3 or 4" should read 2 or 3 Column 6, line 42, "carried" should read "carrier". Column 8, line 4, "2-[allyl-" should read --2-[(allyl- Signed and sealed this 18th day of February 1975.

(SEAL) Attest C. MARSHALL DANN RUTH C. .MASON Commissioner of Patents Attesting Officer v and Trademarks 

